Marburg virus is one of the first discovered filovirus discovered. Filoviruses are negative-single stranded RNA that cause hemorrhagic fevers. [1] The Marburg virus, as well as Ebola virus, has 7 genes with an approximate weight of 19kb. Filoviruses are categorized into three main categories: ebolavirus, Marburgvirus, and cuevavirus. [1] Marburgvirus is just as lethal as Ebola virus with a fatality rate of 70-90% fatality. Marburg was discovered in 1967 in Marburg, Germany when workers at a laboratory were handling tissue samples from African Green Monkeys and the monkeys used for their study were carrying the Marburg virus. The virus typically travels through physical contact and bodily fluids, but there has been documented cases where the virus was spread through aerosol. The virus causes hemorrhagic fever. The virus has an incubation (dormant) time of 5 to 10 days. After the fifth day, victims experience massive hemorrhaging, extreme weight loss, inflamed pancreases, and multi-organ dysfunction. [1] Antiviral drugs to combat filoviruses are few. References: 1. Bradfute, S. B.; Warfield, K. L.; Bray, M., Mouse models for filovirus infections. Viruses2012,4 (9), 1477-508. 2. National Center for Biotechnology Information. PubChem Compound Database; CID=5477931, https://pubchem. Ncbi.nlm.nih.gov/compound/54477931 (accessed Feb. 4, 2017). 3. Bradfute, S. B.; Swanson, P. E.; Smith, M. A.; Watanabe, E.; McDunn, J. E.; Hotchkiss, R. S.; Bavari, S., Mechanisms and consequences of ebolavirus-induced lymphocyte apoptosis. J Immunol2010,184 (1), 327-35. 4. Launay, S.; Hermine, O.; Fontenay, M.; Kroemer, G.; Solary, E.; Garrido, C., Vital functions for lethal caspases. Oncogene2005,24 (33), 5137-48. 5. De Maria, R.; Zeuner, A.; Eramo, A.; Domenichelli, C.; Bonci, D.; Grignani, F.; Srinivasula, S. M.; Alnemri, E. S.; Testa, U.; Peschle, C., Negative regulation of erythropoiesis by caspase-mediated cleavage of GATA-1. Nature1999,401 (6752), 489-93. 6. Olejnik, J.; Ryabchikova, E.; Corley, R. B.; Mühlberger, E., Intracellular events and cell fate in filovirus infection. Viruses2011,3 (8), 1501-31.
Function in a normal cell: Caspase-8 is used in apoptosis in cells, but caspase-8 is also necessary in the proliferation of red blood cells and lymphocytes, white blood cells.
Drug Information:
Schematic figure of drug:
Figure 1. The molecule used in FGI-103 to combat against filoviruses.
Formula: C19H16N6O Molecular weight: 344.369 g/mol CAS Number: 907169-69-1 Delivery method: IV, or orally Side effects: Theoretically FGI-103 seems to have potential to combat against the filoviruses, there have been no human experiments or clinical trials, so side effects are not known. But, from past research about caspase-8 and its function in the body, one can guess that the side effects will cause shortness of breath due to the lack of red blood cells, potential to contract other diseases due to a weakened immune system from a lack of lymphocytes to fight in the body, and even potentially cancer, because caspase-8 is a caspase used in apoptosis, but with a lack of caspase-8 apoptosis will be stunted which has a potential to cause unrestricted growth, or cancerous tumors.
Other names: 2-[(E)-2-(5-carmamimidoyl-1-benzofuran-2-yl)-vinyl]-3H-benzimidazole-5-carboximidamide
Maker or company: Functional Genetics, Inc.
Is it patented? The drug does have a patent that has been published in 2009
Clinical Trials Info: There are no human clinical trials yet. FGI-103 has only been tested on mice. Origin: Synthetically made in the lab. Alternatives to this drug: FIG-104, TKM-Marburg, LJ-001
Miscellaneous:
Figure 3. Graphs depicting the effectiveness of different drugs inhibiting the different caspases. FGI-103 is numbered 369723 in the data table.
FGI-103 inhibits many caspases within the body, but to varying degrees. As seen in the graph, FGI-103 inhibits caspase-8 the best. When caspase-8 is mutated or absent from the body, lymphocytes cease to continuously proliferate, and erythroblasts will also have decreased proliferation. Both of those symptoms can help combat filoviruses, because filoviruses, such as Marburg virus, target macrophages, monocytes, and dendritic cells before spreading to the liver, spleen, and other organs through the blood stream and lymph flow. [6] Macrophages are large phagocytotic cells that are found in tissues and white blood cells. Monocytes are large phagocytotic white blood cells. Lastly, dendritic cells are cells that act as messengers within the immune system. FGI-103 has the potential to stop the progression of Marburg from spreading in the body and causing death in patients is from the fact that FGI-103 inhibits caspase-8 which stops the proliferation of all the cells that Marburg, and other filoviruses, attacks and attaches to first.
Other uses: Can be successful in countering other filoviruses such as Ebola, and can cure Pox, Rift Valley Fever, and Lassa Fever.
Disease/Drug of interest:
Motivation and Background:
Marburg virus is one of the first discovered filovirus discovered. Filoviruses are negative-single stranded RNA that cause hemorrhagic fevers. [1] The Marburg virus, as well as Ebola virus, has 7 genes with an approximate weight of 19kb. Filoviruses are categorized into three main categories: ebolavirus, Marburgvirus, and cuevavirus. [1] Marburgvirus is just as lethal as Ebola virus with a fatality rate of 70-90% fatality. Marburg was discovered in 1967 in Marburg, Germany when workers at a laboratory were handling tissue samples from African Green Monkeys and the monkeys used for their study were carrying the Marburg virus. The virus typically travels through physical contact and bodily fluids, but there has been documented cases where the virus was spread through aerosol. The virus causes hemorrhagic fever. The virus has an incubation (dormant) time of 5 to 10 days. After the fifth day, victims experience massive hemorrhaging, extreme weight loss, inflamed pancreases, and multi-organ dysfunction. [1] Antiviral drugs to combat filoviruses are few.References:
1. Bradfute, S. B.; Warfield, K. L.; Bray, M., Mouse models for filovirus infections. Viruses 2012, 4 (9), 1477-508.
2. National Center for Biotechnology Information. PubChem Compound Database; CID=5477931, https://pubchem. Ncbi.nlm.nih.gov/compound/54477931 (accessed Feb. 4, 2017).
3. Bradfute, S. B.; Swanson, P. E.; Smith, M. A.; Watanabe, E.; McDunn, J. E.; Hotchkiss, R. S.; Bavari, S., Mechanisms and consequences of ebolavirus-induced lymphocyte apoptosis. J Immunol 2010, 184 (1), 327-35.
4. Launay, S.; Hermine, O.; Fontenay, M.; Kroemer, G.; Solary, E.; Garrido, C., Vital functions for lethal caspases. Oncogene 2005, 24 (33), 5137-48.
5. De Maria, R.; Zeuner, A.; Eramo, A.; Domenichelli, C.; Bonci, D.; Grignani, F.; Srinivasula, S. M.; Alnemri, E. S.; Testa, U.; Peschle, C., Negative regulation of erythropoiesis by caspase-mediated cleavage of GATA-1. Nature 1999, 401 (6752), 489-93.
6. Olejnik, J.; Ryabchikova, E.; Corley, R. B.; Mühlberger, E., Intracellular events and cell fate in filovirus infection. Viruses 2011, 3 (8), 1501-31.
External links:
https://docs.google.com/viewer?url=patentimages.storage.googleapis.com/pdfs/US20110152343.pdfhttp://www.jimmunol.org/content/jimmunol/184/1/327.full.pdf
http://www.nature.com/onc/journal/v24/n33/full/1208524a.html
http://www.mdpi.com/1999-4915/4/9/1477/htm
Target Information:
Size: 18 kDa
Location: Found everywhere in the body.
Function in a normal cell: Caspase-8 is used in apoptosis in cells, but caspase-8 is also necessary in the proliferation of red blood cells and lymphocytes, white blood cells.
Drug Information:
Schematic figure of drug:
Formula: C19H16N6O
Molecular weight: 344.369 g/mol
CAS Number: 907169-69-1
Delivery method: IV, or orally
Side effects: Theoretically FGI-103 seems to have potential to combat against the filoviruses, there have been no human experiments or clinical trials, so side effects are not known. But, from past research about caspase-8 and its function in the body, one can guess that the side effects will cause shortness of breath due to the lack of red blood cells, potential to contract other diseases due to a weakened immune system from a lack of lymphocytes to fight in the body, and even potentially cancer, because caspase-8 is a caspase used in apoptosis, but with a lack of caspase-8 apoptosis will be stunted which has a potential to cause unrestricted growth, or cancerous tumors.
Other names: 2-[(E)-2-(5-carmamimidoyl-1-benzofuran-2-yl)-vinyl]-3H-benzimidazole-5-carboximidamide
Maker or company: Functional Genetics, Inc.
Is it patented? The drug does have a patent that has been published in 2009
Clinical Trials Info: There are no human clinical trials yet. FGI-103 has only been tested on mice.
Origin: Synthetically made in the lab.
Alternatives to this drug: FIG-104, TKM-Marburg, LJ-001
Miscellaneous:
FGI-103 inhibits many caspases within the body, but to varying degrees. As seen in the graph, FGI-103 inhibits caspase-8 the best. When caspase-8 is mutated or absent from the body, lymphocytes cease to continuously proliferate, and erythroblasts will also have decreased proliferation. Both of those symptoms can help combat filoviruses, because filoviruses, such as Marburg virus, target macrophages, monocytes, and dendritic cells before spreading to the liver, spleen, and other organs through the blood stream and lymph flow. [6] Macrophages are large phagocytotic cells that are found in tissues and white blood cells. Monocytes are large phagocytotic white blood cells. Lastly, dendritic cells are cells that act as messengers within the immune system. FGI-103 has the potential to stop the progression of Marburg from spreading in the body and causing death in patients is from the fact that FGI-103 inhibits caspase-8 which stops the proliferation of all the cells that Marburg, and other filoviruses, attacks and attaches to first.
Other uses: Can be successful in countering other filoviruses such as Ebola, and can cure Pox, Rift Valley Fever, and Lassa Fever.